The 4,5-epoxymorphinan derivative represented by the general formula (I) or the pharmacologically acceptable acid addition salt thereof that is the effective ingredient of the present invention has a remarkable antipruritic effect, and has been disclosed as an effective compound for a drug of treating pruritus in various diseases associated with the pruritus (e.g., see patent Document 1 [U.S. Pat. No. 3,531,170]). However, it has been known that the 4,5-epoxymorphinan derivative is chemically unstable to light, heat and oxygen (e.g., see Patent Document 2 [International Publication WO99/02158 Pamphlet]). Therefore, it has been necessary to develop a preparation having the good stability in order to assure its quality.
Conventionally, as methods for stabilizing various morphinan compounds including morphine, a technique of adding a basic ingredient to morphine (e.g., see Patent Document 3 [JP Hei-2-160719-A]), methods of combining an antioxidant such as sodium thiosulfate and tocopherol with naloxone (e.g., Patent Document 4 [International Publication WO98/35679 Pamphlet]), methods of adding a chelating agent and a citrate buffer to methylnaltrexone (e.g., see Patent Document 5 [JP 2006-522818]) and methods of blending an organic acid and a chelate forming agent to naltrexone hydrochloride (e.g., see Patent Document 6 [JP 2005-531515]) have been disclosed. However, these reports do not describe a stabilization effect of hydroxypropylcellulose having a low degree of substitution, which is a particular disintegrant, and it does not necessarily perform such an effect. The technique of stabilizing the 4,5-epoxymarphinan derivative has been disclosed in detail in Patent Document 2, and it has been described that a stable pharmaceutical composition is obtained by containing sugars or sugar alcohols, an antioxidant such as sodium thiosulfate, or the like. However, nothing is described for types and blended amounts of disintegrants and binders that are effective for the stabilization; thus, the stabilization effect given to a solid preparation by hydroxypropylcellulose having the low degree of substitution, which is the particular disintegrant, has not been revealed.
Meanwhile, an orally disintegrating tablet that can be taken without water, which aims at improving a dosing compliance, has been disclosed as the solid preparation containing sugars or sugar alcohols such as lactose, mannitol or erythritol and containing hydroxypropylcellulose having the low degree of substitution as the disintegrant. The following have been disclosed: a composition that contains the effective ingredient, the sugar alcohols and hydroxypropylcellulose having the low degree of substitution, having the degree of substitution and a bulk density of a particular hydroxypropoxyl group and enhances a disintegrating property (e.g., see Patent Document 7 [JP Hei-11-43429-A], Patent Document 8 [JP 2001-328948-A]); or an external lubricant tableting method in which the amount of added magnesium stearate is minimized in order to shorten a disintegrating time in an oral cavity (e.g., see Patent Document 9 [International Publication WO2003/103713 Pamphlet]); the technique that defines an ethanol permeation speed in a lubricant (e.g., see Patent Document 10 [International Publication WO2001/076565 Pamphlet]). However, the solid preparation of the present invention need not be disintegrated in the oral cavity, and thus is essentially different from these problems. More importantly, these reports do not describe sodium thiosulfate, and do no describe its effect on stabilization; therefore, the present invention can not be conceived easily from these reports.
Meanwhile, a technique of preventing degradation of the drug or functional change of functional particles due to compression by using spray dry powders containing the sugar alcohol has been disclosed (e.g., see Patent Document 11 [International Publication WO2002/070013 Pamphlet).
However, in the above report, sodium thiosulfate is not described, and the stabilization effect given to a storage stability of the drug by addition of the sugar alcohol or sodium thiosulfate is not described at all.    Patent Document 1: U.S. Pat. No. 3,531,170    Patent Document 2: International Publication WO99/02158 Pamphlet    Patent Document 3: JP Hei-2-160719-A    Patent Document 4: International Publication WO98/35679 Pamphlet    Patent Document 5: JP 2006-522818    Patent Document 6: JP 2005-531515    Patent Document 7: JP Hei-11-43429-A    Patent Document 8: JP 2001-328948-A    Patent Document 9: International Publication WO2003/103713 Pamphlet    Patent Document 10: International Publication WO2001/076565 Pamphlet    Patent Document 11: International Publication WO2002/070013 Pamphlet